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PMID: 23258414 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Reconstitution of the vital functions of Munc18 and Munc13 in neurotransmitter release.

Science (New York, N.Y.) ·Vol. 339 ·No. 6118 ·2013-01-25 ·Pages 421-5

Ma C, Su L, Seven AB, Xu Y, Rizo J

Abstract

Neurotransmitter release depends critically on Munc18-1, Munc13, the Ca(2+) sensor synaptotagmin-1, and the soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptors (SNAREs) syntaxin-1, synaptobrevin, and SNAP-25. In vitro reconstitutions have shown that syntaxin-1-SNAP-25 liposomes fuse efficiently with synaptobrevin liposomes in the presence of synaptotagmin-1-Ca(2+), but neurotransmitter release also requires Munc18-1 and Munc13 in vivo. We found that Munc18-1 could displace SNAP-25 from syntaxin-1 and that fusion of syntaxin-1-Munc18-1 liposomes with synaptobrevin liposomes required Munc13, in addition to SNAP-25 and synaptotagmin-1-Ca(2+). Moreover, when starting with syntaxin-1-SNAP-25 liposomes, NSF-α-SNAP disassembled the syntaxin-1-SNAP-25 heterodimers and abrogated fusion, which then required Munc18-1 and Munc13. We propose that fusion does not proceed through syntaxin-1-SNAP-25 heterodimers but starts with the syntaxin-1-Munc18-1 complex; Munc18-1 and Munc13 then orchestrate membrane fusion together with the SNAREs and synaptotagmin-1-Ca(2+) in an NSF- and SNAP-resistant manner.

MeSH Terms
Animals Calcium/metabolism Humans Liposomes Membrane Fusion Models, Biological Munc18 Proteins/metabolism Nerve Tissue Proteins/metabolism Neurotransmitter Agents/metabolism Protein Binding Protein Multimerization R-SNARE Proteins/metabolism Rats Synaptic Vesicles/metabolism Synaptosomal-Associated Protein 25/metabolism Synaptotagmin I/metabolism Syntaxin 1/metabolism
Chemicals
Liposomes Munc18 Proteins Nerve Tissue Proteins Neurotransmitter Agents R-SNARE Proteins SNAP25 protein, human Stx1a protein, rat Stxbp1 protein, rat Synaptosomal-Associated Protein 25 Synaptotagmin I Syntaxin 1 Unc13a protein, rat Calcium
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Ma Cong
Key Laboratory of Molecular Biophysics, Ministry of Education, and Institute of Biophysics and Biochemistry, Huazhong University of Science and Technology, Wuhan 430074, China. [email protected]
Su Lijing
Seven Alpay B
Xu Yibin
Rizo Josep
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Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.1230473
Email
[email protected]
Published
2013-01-25
Epub
2012-00-20
Pages
421-5
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC3733786
Subset
IM
Grants
NINDS NIH HHS · R01 NS037200 · United States
NINDS NIH HHS · R01 NS040944 · United States
NINDS NIH HHS · NS40944 · United States
NINDS NIH HHS · NS37200 · United States
Corrections
CommentIn
PMID: 23349281
External Links
PubMed source DOI: 10.1126/science.1230473 PMC Full Text View journal details
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